Phase I trial of CRD3874-SI, a systemically administered STING agonist, in patients with advanced solid tumors.

TPS2690 Background: Identifying novel approaches that harness and augment anti-tumor immune responses represents an important area of ongoing research and drug development. Stimulator of interferon genes (STING) is an endoplasmic protein receptor that acts as an innate immune mediator by generating protective type 1 interferons when cytosolic DNA is detected in cells. STING also channels protons across golgi membranes promoting autophagy and pyroptosis. CRD3874-SI is a first in class small molecule allosteric STING agonist and potent activator of all five human STING variants that promotes the release of inflammatory cytokines from downstream interferon genes. It has demonstrated promising pre-clinical anti-cancer activity in several tumor mouse models. CRD3874-SI demonstrated high levels of systemic safety in cynomolgus monkeys, thought to be related to its ability to inhibit STING proton channel activity. Methods: This is a single institution, phase 1a/b study of CRD3874-SI in patients with advanced sarcoma and Merkel cell carcinoma who have received at least one line of prior therapy. The dose escalation phase will explore the safety and tolerability of CRD3874-SI across 6 dose levels following a standard 3+3 design. Dose expansion in subtype specific sarcoma and Merkel cell carcinoma is planned on completion of the dose escalation phase of the study. CRD3874-SI will be administered by intravenous infusion once per week for 2 cycles. From cycle 3 onwards, participants will receive three consecutive weekly infusions followed by one week break, over a 28-day treatment cycle. The primary objective is to assess the safety and tolerability of CRD3874-SI by determining the maximum tolerated dose, recommended phase 2 dose and schedule of administration. Secondary objectives include further defining the safety profile, examining the pharmacokinetics and pharmacodynamics (CXCL10 analysis) of CRD3874-SI and evaluating the efficacy of CRD3874-SI as determined by best objective response rate and clinical benefit rate per RECIST v 1.1. Treatment will continue for up 6 cycles or until disease progression or unacceptable toxicity. Cross sectional imaging will be used to measure clinical activity. Adverse events will be evaluated using NCI-CTCAE v5.0 criteria. This study is currently open to enrollment and dosing has commenced. Clinical trial information: NCT06021626 .